Cyanopyrroles

ABSTRACT

This invention provides a progesterone receptor antagonist of formula 1 having the structure  
                 
 
wherein, T is O, S, or absent; R 1 , and R 2  are each, independently, hydrogen, alkyl, substituted alkyl; or R 1  and R 2  are taken together form a ring and together contain —CH 2 (CH 2 ) n CH 2 —, —CH 2 CH 2 CMe 2 CH 2 CH 2 —, —O(CH 2 ) p CH 2 —, —O(CH 2 ) q O—, —CH 2 CH 2 OCH 2 CH 2 —, or —CH 2 CH 2 NR 7 CH 2 CH 2 —; n=1-5; p=1-4; q=1-4; R 3  is hydrogen, OH, NH 2 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or COR A ; R A  is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R 4  is hydrogen, halogen, CN, NH 2 , alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R 5  is hydrogen, alkyl, or substituted alkyl; R 6  is hydrogen, alkyl, substituted alkyl, or COR B ; R B  is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R 7  is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/342,719, filed Jan. 15, 2003, which is a divisional of U.S. patentapplication Ser. No. 10/043,513, filed Jan. 9, 2002, now U.S. Pat. No.6,562,857, which is a divisional of U.S. patent application Ser. No.09/552,544, filed Apr. 19, 2000, now U.S. Pat. No. 6,407,101, whichclaims the benefit of the priority of U.S. patent application Ser. No.60/183,050, filed May 4, 1999, now abandoned.

BACKGROUND OF THE INVENTION

Intracellular receptors (IR) form a class of structurally related generegulators known as “ligand dependent transcription factors” (R. M.Evans, Science, 240, 889, 1988). The steroid receptor family is a subsetof the IR family, including progesterone receptor (PR), estrogenreceptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), andmineralocorticoid receptor (MR).

The natural hormone, or ligand, for the PR is the steroid progesterone,but synthetic compounds, such as medroxyprogesterone acetate orlevonorgestrel, have been made which also serve as ligands. Once aligand is present in the fluid surrounding a cell, it passes through themembrane via passive diffusion, and binds to the IR to create areceptor/ligand complex. This complex binds to specific gene promoterspresent in the cell's DNA. Once bound to the DNA the complex modulatesthe production of mRNA and protein encoded by that gene.

A compound that binds to an IR and mimics the action of the naturalhormone is termed an agonist, whilst a compound that inhibits the effectof the hormone is an antagonist.

PR agonists (natural and synthetic) are known to play an important rolein the health of women. PR agonists are used in birth controlformulations, typically in the presence of an ER agonist, alternativelythey may be used in conjunction with a PR antagonist. ER agonists areused to treat the symptoms of menopause, but have been associated with aproliferative effect on the uterus that can lead to an increased risk ofuterine cancers. Co-administration of a PR agonist reduces or ablatesthat risk.

Jones et al (U.S. Pat. No. 5,688,810) described the PR antagonistdihydroquinoline A.

Jones et al described the enol ether B (U.S. Pat. No. 5,693,646) as a PRligand.

Jones et al described compound C (U.S. Pat. No. 5,696,127) as a PRligand.

Zhi et al described lactones D, E and F as PR antagonists (J. Med. Chem.41, 291, 1998).

Zhi et al described the ether G as a PR antagonist (J. Med. Chem. 41,291, 1998).

Combs et al disclosed the amide H as a ligand for the PR (J. Med. Chem.38, 4880, 1995).

Perlman et al described the vitamin D analog I as a PR ligand(Tetrahedron. Lett. 35, 2295, 1994).

Hamann et al described the PR antagonist J (Ann. N.Y. Acad. Sci. 761,383, 1995).

Chen et al described the PR antagonist K (Chen et al, POI-37, 16^(th)Int. Cong. Het. Chem., Montana, 1997).

Kurihari et al described the PR ligand L (J. Antibiotics 50, 360, 1997).

Kuhla et al claimed the oxindole M as a cardiotonic (WO 86/03749).

Weber claimed the oxindole N for cardiovascular indications (WO91/06545).

Fischer et al claim a preparation for making compounds which include thegeneric structure O (U.S. Pat. No. 5,453,516).

Singh et al described the PDE III inhibitor P (J. Med. Chem. 37, 248,1994).

Andreani et al described the cytotoxic agent Q (Acta. Pharn. Nord. 2,407, 1990).

Binder et al described structure R which is an intermediate forpreparing COX II inhibitors (WO 97/13767).

Walsh (A. H. Robins) described the oxindole S as an intermediate (U.S.Pat. No. 4,440,785, U.S. Pat. No. 4,670,566).

Bohm et al claim the oxindole T as cardiovascular agents (WO 91/06545).

Bohm et al include the generic structure U (WO 91/04974).

A Japanese patent contains the generic structure V (JP 63112584 A).

Boar et al described the dioxolane W as an intermediate for preparationof acetyl-cholinesterase inhibitors (WO 93/12085 A1).

Kende et al described methodology for preparing 3,3-substitutedoxindoles, e.g., X, that was utilized in the present invention (Synth.Commun. 12, 1, 1982).

There are numerous literature reports that disclose a number ofbenzoxazin-2-ones. However, none of these examples in these patentscontain substituents necessary for the compounds to be active asprogesterone receptor modulators.

Among these publications, Narr et al (German Patent No. DE 3633861, CA109:22973) discussed imidazobenzoxazinones, e.g. Y, as cardotonics.Benzoxazin-2-ones, such as brofoxine (Z), being active as an anxiolyticwas reported by Hartmann et al (Proc. West. Pharmacol. Soc. 21, 51-55(1978)). More recently, a number of patents (e.g., Young et alWO95/20389; Christ et al. WO98/14436) claimed quinazolin-2-ones andbenzoxazin-2-ones such as compounds AA and BB as inhibitors of HIVreverse transcriptase.

DESCRIPTION OF THE INVENTION

This invention provides progesterone receptor agonists of Formula 1having the structure:

wherein, T is O, S, or absent; R₁, and R₂ are each, independently,hydrogen, alkyl, substituted alkyl; or R₁ and R₂ are taken together forma ring and together contain —CH₂(CH₂)_(n)CH₂—, —CH₂CH₂CMe₂CH₂CH₂—,—O(CH₂)_(p)CH₂—, —O(CH₂)_(q)O—, —CH₂CH₂OCH₂CH₂—, or —CH₂CH₂NR₇CH₂CH₂—;n=1-5; p=1-4; q=1-4; R₃ is hydrogen, OH, NH₂, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or COR^(A);R^(A) is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,aminoalkyl, or substituted aminoalkyl; R₄ is hydrogen, halogen, CN, NH₂,alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, orsubstituted aminoalkyl; R₅ is hydrogen, alkyl, or substituted alkyl;

-   -   R₆ is hydrogen, alkyl, substituted alkyl, or COR^(B); R^(B) is        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        aminoalkyl, or substituted aminoalkyl;    -   R₇ is hydrogen or alkyl;    -   or a pharmaceutically acceptable salt thereof, which are useful        for contraception, in the treatment of fibroids, endometriosis,        breast, uterine, ovarian and prostate cancer, and post        menopausal hormone replacement therapy.

Desired compounds of this invention are those having the structure:

wherein, T is O, or absent; R₁, and R₂ are each, independently,hydrogen, alkyl, substituted alkyl; or R₁ and R₂ are taken together forma ring and together contain —CH₂(CH₂)_(n)CH₂—; n=1-5; R₃ is hydrogen; R4is hydrogen or halogen; R₅ is hydrogen or alkyl; R6 is hydrogen oralkyl; or a pharmaceutically acceptable salt thereof.

The compounds of this invention may contain an asymmetric carbon atomand some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereoisomers. While shown without respect to stereochemistry inFormula 1, the present invention includes such optical isomers anddiastereoisomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof.

The compounds of this invention have been shown to act as competitiveinhibitors of progesterone binding to the PR and act as agonists infunctional models, either/or in-vitro and in-vivo. These compounds maybe used for contraception, in the treatment of fibroids, endometriosis,breast, uterine, ovarian and prostate cancer, and post menopausalhormone replacement therapy.

The term “alkyl” is used herein to refer to both straight- andbranched-chain saturated aliphatic hydrocarbon groups having 1-6 carbonatoms; “alkenyl” includes both straight- and branched-chain alkyl groupsof 2-6 carbon atoms containing at least one carbon-carbon double bond;“alkynyl” group includes both straight- and branched-chain alkyl groupsof 2-6 carbon atoms with at least one carbon-carbon triple bond.

The terms “substituted alkyl”, “substituted alkenyl”, and “substitutedalkynyl” refer to alkyl, alkenyl, and alkynyl as containing one or moresubstituents from the group including halogen, CN, OH, NO₂, amino, aryl,heterocyclic, substituted aryl, substituted heterocyclic, alkoxy,aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino,arylthio. These substituents may be attached to any carbon of alkyl,alkenyl, or alkynyl group provided that the attachment constitutes astable chemical moiety.

The term “thioalkyl” is used herein to refer to the SR group, where R isalkyl or substituted alkyl.

The term “alkoxy” is used herein to refer to the OR group, where R isalkyl or substituted alkyl.

The term “aryloxy” is used herein to refer to the OR group, where R isaryl or substituted aryl.

The term “alkylcarbonyl” is used herein to refer to the RCO group, whereR is alkyl or substituted alkyl.

The term “alkylcarboxy” is used herein to refer to the COOR group, whereR is alkyl or substituted alkyl. This term is also referred to asalkoxycarbonyl.

The term “aminoalkyl” refers to both secondary and tertiary amineswherein the alkyl or substituted alkyl groups may be either same ordifferent and the point of attachment is on the nitrogen atom.

The term “halogen” is defined as Cl, Br, F, and I.

Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids. Salts may also beformed from inorganic bases, preferably alkali metal salts, for example,sodium, lithium, or potassium, and organic bases, such as ammonium,mono-, di-, and trimethylammonium, mono-, di- and triethylammonium,mono-, di- and tripropylammonium (iso and normal),ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium,benzylammonium, dibenzylammonium, piperidinium, morpholinium,pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium,1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, mono-,di- and triethanolammonium, ethyl diethanolammonium,n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium,phenylmonoethanolammonium, and the like.

The compounds of this invention were be prepared according to thefollowing schemes from commercially available starting materials orstarting materials which can be prepared using literature procedures.These schemes show the preparation of representative compounds of thisinvention.

According to scheme 1, commercially available oxindole 4 is treated witha strong organo-metallic base (e.g., butyl lithium, lithiumdiisopropylamide, potassium hexamethyldisilazide) in an inert solvent(e.g. THF, diethyl ether) under nitrogen at reduced temperature (ca.−20° C.) (Kende, et al, Synth. Commun. 12, 1, 1982). The resultingdi-anion then is treated with excess electrophile such as an alkylhalide, preferably an iodide. If R₁ and R₂ are to be joined such as theproduct 5 contains a spirocycle at position 3, then the electrophileshould be bifunctional, i.e. a diiodide. Subsequent bromination of 5proceeds smoothly with bromine in acetic acid (an organic co-solventsuch as dichloromethane may be added as required) in the presence ofsodium acetate, to afford the aryl bromide 6. The bromide 6 is reactedwith a palladium salt (e.g., tetrakis(triphenylphosphine)palladium(0) orpalladium acetate), in a suitable solvent (e.g., THF, dimethoxyethane,acetone, ethanol or toluene) at room temperature under an inertatmosphere (argon, nitrogen). The mixture is then treated with pyrrole2-boronic acid (Synthesis 613, 1991) and a base (potassium carbonate,triethylamine, potassium phosphate) in water or fluoride source (cesiumfluoride) under anhydrous conditions. Treatment of the biaryl compound 7with chlorosulfonyl isocyanate followed by an excess of DMF at lowtemperature produces the protected cyanopyrrole 8. Removal of thetert-butyloxycarbonyl (BOC) protecting group via standard conditions(e.g., TFA/dichloromethane, aqueous NaOH, thermolysis) produces therequired final product which is purified by standard means.

As depicted in Scheme 2, an appropriately substituted ortho-aminobenzoic acid, or derivative (such as ethyl ester) 10 is treated with asuitable organometallic reagent, e.g., Grignard reagent, in appropriatenonprotic solvents (e.g., THF, ether, toluene) under an inert atmospheresuch as argon or nitrogen at −78° C. to room temperature to giveortho-amino carbinol 11. Ring closure of carbinol 11 to yieldbenzoxazin-2-ones 12 is commonly effected by a condensing agent (e.g.,carbonyldiimidazole, phosgene, dimethylcarbonate, diethylcarbonate) in asuitable nonprotic solvent (e.g., THF, ether, toluene) at temperaturesin the range of room temperature to 65° C. The pyrrole ring is attachedto this platform by employing a suitable coupling reaction (e.g.,Suzuki, Stille) to give the biaryl 13. These reactions are performed inthe presence of suitable catalyst (e.g., palladium or nickel complexesoften with phosphino ligands, e.g., Ph₃P, dppf, dppe or palladium saltssuch as palladium acetate) and a base: the commonly used bases include(but are not limited to) sodium bicarbonate, sodium carbonate, potassiumphosphate, barium carbonate, potassium acetate, or cesium fluoride. Themost commonly used solvents in these reactions include benzene, DMF,isopropanol, ethanol, DME, ether, acetone or a mixture of any one ofthese solvent and water. The coupling reaction generally is executedunder an inert atmosphere such as nitrogen or argon at temperaturesranging from room temperature to 95° C. Treatment of the biaryl compound13 with chlorosulfonyl isocyanate followed by an excess of DMF at lowtemperature produces the protected cyanopyrrole 14. Removal of thetert-butyloxycarbonyl (BOC) protecting group via standard conditions(e.g., TFA/dichloromethane, aqueous NaOH, thermolysis) produces therequired final product 15 which is purified by standard means.

The compounds of this invention are progestational agonists, and aretherefore useful as oral contraceptives (male and female), in hormonereplacement therapy (particularly when combined with an estrogen), inthe treatment of endometriosis, luteal phase defects, benign breast andprostatic diseases and prostatic, breast, ovarian, uterine andendometrial cancers.

The compounds of this invention can be used alone as a sole therapeuticagent or can be used in combination with other agents, such as otherestrogens, progestins, or androgens.

The compounds of this invention can be formulated neat or with apharmaceutical carrier for administration, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard pharmacological practice. Thepharmaceutical carrier may be solid or liquid.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the carrier is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine,low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,lethicins, and oils (e.g. fractionated coconut oil and arachis oil). Forparenteral administration, the carrier can also be an oily ester such asethyl oleate and isopropyl myristate. Sterile liquid carriers are usefulin sterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. The compounds of this invention can also beadministered orally either in liquid or solid composition form.

The compounds of this invention may be administered rectally orvaginally in the form of a conventional suppository. For administrationby intranasal or intrabronchial inhalation or insufflation, thecompounds of this invention may be formulated into an aqueous orpartially aqueous solution, which can then be utilized in the form of anaerosol. The compounds of this invention may also be administeredtransdermally through the use of a transdermal patch containing theactive compound and a carrier that is inert to the active compound, isnon toxic to the skin, and allows delivery of the agent for systemicabsorption into the blood stream via the skin. The carrier may take anynumber of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments may be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the active ingredient may also besuitable. A variety of occlusive devices may be used to release theactive ingredient into the blood stream such as a semipermeable membranecovering a reservoir containing the active ingredient with or without acarrier, or a matrix containing the active ingredient. Other occlusivedevices are known in the literature.

The dosage requirements vary with the particular compositions employed,the route of administration, the severity of the symptoms presented andthe particular subject being treated. Based on the results obtained inthe standard pharmacological test procedures, projected daily dosages ofactive compound would be 0.02 μg/kg-750 μg/kg. Treatment will generallybe initiated with small dosages less than the optimum dose of thecompound. Thereafter the dosage is increased until the optimum effectunder the circumstances is reached; precise dosages for oral,parenteral, nasal, or intrabronchial administration will be determinedby the administering physician based on experience with the individualsubject treated. Preferably, the pharmaceutical composition is in unitdosage form, e.g. as tablets or capsules. In such form, the compositionis sub-divided in unit dose containing appropriate quantities of theactive ingredient; the unit dosage forms can be packaged compositions,for example, packaged powders, vials, ampoules, pre filled syringes orsachets containing liquids. The unit dosage form can be, for example, acapsule or tablet itself, or it can be the appropriate number of anysuch compositions in package form.

The following provides the preparation of representative compounds ofthis invention.

EXAMPLE 15-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1H-pyrrole-2-carbonitrile

A solution of 2-amino-5-bromobenzoic acid (10 g, 46 mmol) in dry THF(200 mL) was treated at −78° C. under nitrogen with a solution ofmethylmagnesium bromide in ether (3.0 M, 90 mL, 270 mmol). The reactionmixture was slowly warmed to ambient temperature, kept stirring for 48hours under nitrogen and then poured into a cold 0.5 N aqueoushydrochloride solution (300 mL). The mixture was neutralized withaqueous 1 N sodium hydroxide solution and ethyl acetate (300 mL) wasadded. The organic layer was separated and aqueous layer was extractedwith ethyl acetate (3×100 mL). The combined organic layers were washedwith brine and dried (MgSO₄). After removal of solvent in vacuo, theresidue was purified by a silica gel flash chromatography (hexane:ethylacetate/3:2) to give 2-(2-amino-5-bromophenyl)propan-2-ol as anoff-white solid (6 g, 57%): mp 62-63° C.; ¹H-NMR (CDCl₃) δ 7.19 (d, 1H,J=2.3 Hz), 7.12 (dd, 1H, J=8.4, 2.3 Hz), 6.51 (d, 1H, J=8.4 Hz), 4.70(s, 2H), 1.82 (s, 1H), 1.65 (s, 6H).

To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (18 g, 78 mmol) indry THF (150 mL) was added 1,1′-carbonyldiimidazole (15.5 g, 94 mmol)under nitrogen. The reaction solution was heated at 50° C. overnight.The solvent was removed in vacuo and the residue was dissolved in ethylacetate (100 mL). The solution was washed with 1N aqueous hydrochloridesolution (2×40 mL), brine (20 mL), and dried with MgSO₄. After removalof the solvent in vacuo,6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was obtainedas a white solid (20 g, 100%): mp 199-200° C.; ¹H-NMR (DMSO-d₆) δ 10.32(s, 1H, D₂O exchangeable), 7.48 (d, 1H, J=2.1 Hz), 7.43 (dd, 1H, J=8.5,2.1 Hz), 6.84 (d, 1H, J=8.4 Hz), 1.61 (s, 6H).

A solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(5.0 g, 20 mmol) and tetrakis(triphenylphosphine)palladium(0) (580 mg,0.5 mmol) in toluene (200 mL) was stirred under a flow of nitrogen for25 min. To the solution was added sequentially1-tert-butoxycarbonylpyrrole-2-boronic acid (8.24 g, 39 mmol) inabsolute ethanol (50 mL) and potassium carbonate (5.39 g, 39 mmol) inwater (50 mL). The mixture was heated to 80° C. for 16 hours and allowedto cool. The reaction mixture was poured into aqueous saturated sodiumbicarbonate solution (200 mL) and extracted with ethyl acetate (3×200mL). The organic layers were combined, washed with water (200 mL) andbrine (100 mL) and dried over magnesium sulfate. The solution wasfiltered, concentrated in vacuo, and the residue was purified by flashcolumn chromatography on silica gel (30% ethyl acetate/hexane) to give2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-pyrrole-1carboxylicacid tert-butyl ester (4.0 g, 58%) as a tan solid, mp 172-173° C.

To a solution of2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-pyrrole-1-carboxylicacid tert-butyl ester (2.0 g, 5.8 mmol) in THF (anhydrous, 50 mL) at−78° C. was added chlorosulfonyl isocyanate (0.66 mL, 6.7 mmol). After90 minutes, DMF (9 mL, 116 mmol) was added and the reaction was allowedto warm to room temperature. The reaction mixture was poured into water(50 mL) and extracted with ethyl acetate (2×50 mL). The organic layerswere combined, washed with brine (50 mL), dried over magnesium sulfate,filtered and concentrated in vacuo. Purification via flash columnchromatography on silica gel (30% ethyl acetate/hexane) gave2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-cyano-pyrrole-1-carboxylicacid tert-butyl ester (1.1 g, 52%) as a white powder, mp 165-167° C. ¹HNMR (d₆-DMSO, 300 MHz) δ 1.36 (s, 9H), 1.61 (s, 6H), 6.44 (d, 1H, J=3.7Hz), 6.92 (d, 1H, J=8.2 Hz), 7.27-7.32 (m, 2H), 7.36 (‘d’, 1H, J=1.5Hz), 10.36 (s, 1H). MS (EI) m/z 367 [M]⁺.

2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-cyano-pyrrole-1-carboxylicacid tert-butyl ester (1 g, 2.7 mmol) was placed in a 25 mL roundbottomed flask stoppered with a rubber septum and equipped with anitrogen inlet and a needle to allow gaseous outflow. A vigorous flow ofnitrogen was maintained as the flask was placed in an oil bath andheated to 160° C. After 20 minutes at this temperature, the flask wasremoved from the oil bath and allowed to cool. The yellow residue waswashed into a larger flask with dichloromethane/ethyl acetate andadsorbed onto a small amount of silica gel. Purification by flash columnchromatography on silica gel (40% ethyl acetate/hexane) gave the titlecompound (340 mg, 47%) as a yellow powder, mp 241-242° C. ¹H NMR(d₆-DMSO, 300 MHz) δ 1.65 (s, 6H), 6.67 (d, 1H, J=3.9 Hz), 6.91 (d, 1H,J=8.3 Hz), 6.98 (d, 1H, J=3.9 Hz), 7.61 (dd, 1H, J=1.8, 8.3 Hz), 7.65(‘d’, 1H, J=1.6 Hz), 10.32 (s, 1H), 12.54 (bs, 1H). MS (EI) m/z 267 M⁺.Anal. Calcd. For C₁₅H₁₃N₃O₂: C, 67.41; H, 4.90; N, 15.72. Found: C,67.19; H, 4.96; N, 15.35.

EXAMPLE 25-(2′-Oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole

A solution of oxindole (25 g, 0.19 mol) in anhydrous tetrahydrofuran(800 mL) was cooled to −20° C., then n-butyllithium (2.5M in hexanes,152 mL, 0.38 mol) was added slowly followed byN,N,N′,N′-tetramethylethylenediamine (51 mL, 0.38 mol). After 15 min.1,5-diiodopentane (174 g, 0.54 mol) was added slowly and the mixture wasallowed to warm to room temperature. After stirring for 16 hourssaturated aqueous ammonium chloride solution (1L) and EtOAc (1L) wereadded. After 15 minutes, the layers were separated and the aqueous phasewas extracted using EtOAc (×2). The combined organic layers wereextracted with hydrochloric acid (1N), then washed with brine (500 mL),dried (MgSO₄), and concentrated to obtain an oil. The oil was trituratedwith hexane (200 mL) and benzene (20 mL). The precipitate was collectedand dried in vacuo to obtainspiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)one (26.3 g, 69.6%) ascolorless crystals: mp 110-114° C.; ¹H NMR (DMSO-d₆) δ 1.67 (m, 10H),6.84 (d, 1H, J=8 Hz) 6.94 (t, 1H, J=8 Hz), 7.17 (t, 1H, J=8 Hz), 7.44(d, 1H, J=8 Hz), 10.3 (s, 1H).

To a solution of spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (17.6 g,9 mmol) in acetic acid (300 mL) was added sodium acetate (8.0 g, 0.1mol) and bromine (14.6 g, 91 mmol) with stirring. After 30 minutes atroom temperature, the reaction mixture was partitioned between water andEtOAc. The aqueous phase was extracted twice with EtOAc. The combinedorganic layers were washed with water, dried (MgSO₄) and evaporated andthe residue was triturated with hexane. The precipitate was collected,and dried in vacuo to obtain5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (16.5 g, 67%) asoff-white crystals: mp 196-199° C.; ¹H NMR (DMSO-d₆) δ 1.62 (m, 10H),6.8 (d, 1H, J=6.8 Hz), 7.36 (d, 1H, J=8.2, 1.8 Hz), 7.58 (dd, 1H, J=8.2,1.8 Hz), 10.44 (s, 1H).

To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one (3.4 g,12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere, was addedtetrakis(triphenylphosphine)palladium(0) (70 mg, 5 mol %). After 15minutes, 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3eq, 3.31 g, 15.6 mmol) and a solution of K₂CO₃ (2.3 eq, 3.83 g, 27.6mmol) in water (5 mL) were added sequentially. The solution was heatedto 80° C. for 3 hours and allowed to cool. The reaction mixture waspoured into water (200 mL) and extracted with EtOAc (2×100 mL). Theorganic layers were combined, washed with brine (150 mL) and dried overMgSO₄. The solution was filtered, concentrated in vacuo, and the residuewas purified by flash column chromatography on silica gel (eluting with30% EtOAc/hexane) to give2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (3.4 g, 76%) as a white powder, mp 177° C. ¹H NMR(CDCl₃; 300 MHz) δ 1.38 (s, 9H), 1.59-1.93 (m, 10H), 6.18 (m, 1H), 6.23(‘t’, 1H, J=3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21 (d, 1H, J=8 Hz), 7.34 (m,1H), 7.44 (s, 1H), 8.33 (br s, 1H, D₂Oex). MS ((+)-APCI) m/z 367[(M+H)⁺]. Anal. Calcd for C₂₂H₂₆N₂O₃: C, 72.11; H, 7.15; N, 7.64. Found:C, 71.7; H, 7.16; N, 7.5.

To a solution of2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (0.75 g, 2 mmol) in THF (anhydrous, 20 mL) at−78° C. was added chlorosulfonyl isocyanate (1.15 eq, 0.23 mL, 2.3mmol). After 90 min, DMF (20 eq, 3.6 mL, 46 mmol) was added and thereaction was allowed to warm to room temperature. The reaction mixturewas poured into water (50 mL) and extracted with ethyl acetate (2×50mL). The organic layers were combined, washed with brine (50 mL), driedover magnesium sulfate, filtered and concentrated in vacuo. Purificationvia flash column chromatography on silica gel (30% ethyl acetate/hexane)gave5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole-1-carboxylicacid, tert-butyl ester (0.5 g, 63%) as an oil which crystallized fromacetone to give white crystals, mp 156° C. ¹H NMR (d₆-DMSO, 400 MHz) δ1.32 (s, 9H), 1.50 (m, 3H), 1.60-1.70 (m, 5H), 1.75-1.85 (m, 2H), 6.38(d, 1H, J=3.7 Hz), 6.87 (d, 1H, J=7.9 Hz), 7.18 (dd, 1H, J=1.5, 7.9 Hz),7.27 (d, 1H, J=3.7 Hz), 7.48 (d, 1H, J=1.8 Hz), 10.42 (bs, 1H). MS (EI)m/z 391 (M⁺). Anal. Calcd for C₂₃H₂₅N₃O₃: C, 70.57; H, 6.44; N, 10.73.Found: C, 69.82; H, 6.46; N, 10.43.

5-(2′-Oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole-1-carboxylicacid, tert-butyl ester (0.25 g, 0.8 mmol) was placed in a 5 mL roundbottomed flask stoppered with a rubber septum and equipped with nitrogeninlet and a needle to allow gaseous outflow. A vigorous flow of nitrogenwas maintained as the flask was placed in an oil bath and heated to 180°C. After 5 minutes at this temperature, the flask was removed from theoil bath and allowed to cool. The black residue was washed into a largerflask with acetone and adsorbed onto a small amount of silica gel.Purification by flash column chromatography on silica gel (eluting with30% EtOAc/hexane) gave the title compound (95 mg, 51 %) as a yellow oilwhich crystallized from dichloromethane to give a grey powder, mp 239 °C. (dec). ¹H NMR (DMSO-d₆; 300 MHz) δ 1.40-1.90 (m, 10H), 6.60 (m, 1H),6.88 (d, 1H, J=8.1 Hz), 6.95 (m, 1H), 7.56 (dd, 1H, J=1.8, 8.1 Hz), 7.78(d, 1H, J=1.3 Hz), 10.42 (s, 1H), 12.50 (s, 1H). MS (EI) m/z 291 (M⁺).Anal. Calcd for C₁₈H₁₇N₃O₁: C, 74.20; H, 5.88; N, 14.42. Found: C,66.63; H, 5.52; N, 12.46.

EXAMPLE 32-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-cyanopyrrole

To a solution2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylicacid tert-butyl ester (0.39 g, 1.2 mmol) in THF (anhydrous, 9 mL) at−78° C. was added chlorosulfonyl isocyanate (1.15 eq, 0.12 mL, 1.4mmol). After 120 min, DMF (20 eq, 1.8 mL, 23 mmol) was added and thereaction was allowed to warm to room temperature. The reaction mixturewas poured into water (25 mL) and extracted with ethyl acetate (2×50mL). The organic layers were combined, washed with brine (50 mL), driedover magnesium sulfate, filtered and concentrated in vacuo. Purificationvia flash column chromatography on silica gel (1:3 ethyl acetate/hexane)gave2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-cyanopyrrole-1-carboxylicacid tert-butyl ester (0.21 g, 50%) as a white solid: mp 158.6. ¹H NMR(DMSO-d₆; 300 MHz) δ 1.27 (s, 6H), 1.33 (s, 9H), 6.40 (d, 1H, J=3.8 Hz),6.90 (d, 1H, J=8.0 Hz), 7.19 (dd, 1H, J=1.8, 8.0 Hz), 7.30 (d, 1H, J=1.5Hz), 10.50 (s, 1H). MS m/z 350 (M−H)⁻. Calcd for C₁₉H₂₂N₂O₃: C, 68.36;H, 6.02; N, 11.96. Found: C, 66.79; H, 6.03; N, 11.02.

2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylicacid tert-butyl ester (0.18 g, 0.51 mmol) was placed in a 50 mL roundbottomed flask stoppered with a rubber septum and equipped with anitrogen inlet and a needle to allow gaseous outflow. A vigorous flow ofnitrogen was maintained as the flask was placed in an oil bath andheated to 160° C. After 10 minutes at this temperature, the flask wasremoved from the oil bath and allowed to cool. The black residue waswashed into a larger flask with acetone and adsorbed onto a small amountof flurosil. Purification by flash column chromatography on silica gel(eluting with 1:3 acetone: hexane) gave the title compound (118 mg, 92%)as a white solid mp 255.9-257.9° C. ¹H NMR (DMSO-d₆; 300 MHz) δ 1.29 (s,6H), 6.60 (m, 1H), 6.89 (d, 1H, J=8.0 Hz), 6.96 (m, 1H), 7.55 (dd, 1H,J=1.4, 8.1 Hz), 7.69 (bs, 1H), 10.47 (s, 1H), 12.48 (s, 1H). MS m/z 250(M−H)⁻. Calcd for C₂₀H₂₁N₃O₃: C, 71.7; H, 5.21; N, 16.72. Found: C,71.16; H, 5.58; N, 16.09.

EXAMPLE 45-(2′-Oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole

A solution of 5′-bromospiro[cyclopentane-1,3′-[3H]indol]-2′(1H)-one (2.0g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (430 mg, 0.3mmol) in ethylene glycol dimethyl ether (50 mL) was stirred under a flowof nitrogen for 15 minutes. To the solution was added sequentially1-t-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and potassiumcarbonate (2.4 g, 17 mmol) in water (10 mL). The mixture was heated to80° C. for 3 hours and allowed to cool. The reaction mixture was pouredinto water (50 mL) and extracted with ethyl acetate (3×50 mL). Theorganic layers were combined, washed with brine (30 mL) and dried overmagnesium sulfate. The solution was filtered and concentrated in vacuo.Crystallization from 20% ethyl acetate/hexane gave2-(1′,2′-dihydro-2′-oxospiro[cyclopentane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylic acid,tert-butyl ester (2.2 g, 83%) as a white powder, mp 179-180.5° C. ¹H NMR(DMSO-d₆, 400 MHz) δ 1.30 (s, 9H), 1.75-1.98 (m, 8H), 6.16 (dd, 1H,J=1.8, 3.3 Hz), 6.22 (‘t’, 1H, J=3.3, 3.3 Hz), 6.79 (d, 1H, J=7.9 Hz),7.08 (dd, 1H, J=1.8, 7.9 Hz), 7.14 (‘d’, 1H, J=1.5 Hz), 7.28 (dd, J=1.9,3.3 Hz), 10.30 (s, 1H). MS (EI) m/z 352 [M⁺]. Anal. Calcd forC₂₁H₂₄N₂O₃: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.08; H, 6.83; N,7.74.

To a solution of2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (2.2 g, 6.0 mmol) in THF (anhydrous, 25 mL) wasadded at −78° C. chlorosulfonyl isocyanate (0.63 mL, 7.0 mmol). After 90minutes, dimethylformamide (11 mL, 140 mmol) was added and the reactionwas allowed to warm to room temperature. The reaction mixture was pouredinto water (50 mL) and extracted with ethyl acetate (2×50 mL). Theorganic layers were combined, washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo. Purification viaflash column chromatography on silica gel (30% ethyl acetate/hexane)gave5-(2′-oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole-1-carboxylicacid, tert-butyl ester (1.7 g, 75%) as white crystals, mp 167-169° C. ¹HNMR (DMSO-d₆, 400 MHz) δ 1.34 (s, 9H), 1.75-1.98 (m, 8H), 6.39 (d, 1H,J=3.7 Hz), 6.84 (d, 1H, J=7.9 Hz), 7.17 (dd, 1H, J=1.8, 7.9 Hz), 7.28(‘t’, 2H), 10.41 (s, 1H). MS (ESI) mn/z 376 [M−H]⁻. Anal. Calcd. forC₂₂H₂₃N₃O₃: C, 70.01; H, 6.14; N, 11.13. Found: C, 69.67; H, 6.38; N,11.04.

5-(2′-Oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl-2-cyanopyrrole-1-carboxylicacid, tert-butyl ester (1 g, 2.7 mmol) was placed in a 25 mL roundbottomed flask stoppered with a rubber septum and equipped with nitrogeninlet and a needle to allow gaseous outflow. A vigorous flow of nitrogenwas maintained as the flask was placed in an oil bath and heated to 165°C. After 20 minutes at this temperature, the flask was removed from theoil bath and allowed to cool. Crystallization from ethyl ether gave thetitle compound (600 mg, 79%) as a yellow powder, mp 285-286° C. ¹H NMR(DMSO-d₆, 400 MHz) δ 1.75-2.03 (m, 8H), 6.60 (dd, 1H, J=2.4, 3.7 Hz),6.84 (d, 1H, J=8.1 Hz), 6.94 (dd, 1H, J=2.4, 3.7 Hz), 7.52 (dd, 1H,J=1.8, 8.1 Hz), 7.60 (d, 1H, J=1.8 Hz), 10.38 (s, 1H), 12.45 (s, 1H). MS(ESI) m/z 276 [M−H]⁻. Anal. Calcd. For C₁₇H₁₅N₃O: C, 73.63; H, 5.45; N,15.15. Found: C, 73.24; H, 5.34; N, 14.96.

EXAMPLE 55-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2carbonitrile

To a solution of5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile(1 eq, 71 mg, 0.27 mmol) in dimethylformamide (0.5 mL) was addedpotassium carbonate (5 eq, 0.18 g, 0.1.35 mmol). After 10 minutes,iodomethane (3 eq, 0.05 mL, 0.81 mmol) was added and the suspension wasstirred for 2h, poured into water (5 mL) and extracted with ethylacetate (3×5 mL). The layers were separated, the aqueous layer wasextracted with ethyl acetate (3×10 mL) and the combined organic layerwas washed with brine, dried over MgSO₄ and purified by flash columnchromatography on silica gel eluting with 30% ethyl acetate/hexane togive5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile(30 mg, 41%) as a white solid. ¹H NMR (300 MHz, d₆-DMSO) δ 1.64 (s, 6H),3.71 (s, 3H), 6.33 (d, 1H, J=4.1 Hz), 6.98 (d, 1H, J=8.0 Hz), 7.03 (d,1H, J=4.1 Hz), 7.39 (m, 2H), 10.39 (s, 1H). MS (APCI (−)) m/z 280(M−H)⁻. Anal. calcd for C₁₆H₁₅N₃O₂, C, 68.3, H, 5.37, N, 14.9. Found, C,68.4, H, 5.51, N, 14.6.

EXAMPLE 6 General Method A5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-ethyl-1H-pyrrole-2-carbonitrile

To a solution of5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile(1.3 g, 5 mmol) in dimethylformamide (25 ml) was added potassiumcarbonate (1 g, 7.5 mmol), and iodoethane (0.4 ml, 5.1 mmol), and themixture was stirred at room temperature for 3 hours. Ethylacetate andwater were added, the ethylacetate layer was separated, dried overmagnesium sulfate, and concentrated in vacuo. The residue wasrecrystallized from ethylacetate/hexane to afford the title compound,m.p. 200-202° C. (0.4 g, 27%); ¹H-NMR (DMSO-d₆) δ 1.25 (t, J=7.2 Hz,3H), 1.64 (s, 6H), 4.07 (q, J=7.2 Hz, 2H), 6.29 (d, J=4.1 Hz, 1H), 7.0(d, J=8 Hz, 1H), 7.05 (d, J=4.1 Hz, 1H), 7.34 (m, 2H), 10.42 (s, 1H). MS(ESI (−)) m/z 294 (M−H)⁻

EXAMPLE 75-(4,4-dimethyl-2-oxo-1,4-Dihydro-2H-3,1-benzoxazin-6-yl)-1-prop-2-ynyl-1H-pyrrole-2-carbonitrile

5-(4,4-Dimethyl-2-oxo-1,4,dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-2-carbonitrile(0.74 g, 2.8 mmol) and propargylbromide (0.5 g, 4.2 mmol) were reacted,according to General Method A, to afford the title compound, m.p.222-224° C. (0.13 g, 15%). ¹H-NMR (DMSO-d₆) δ 1.65 (s, 6H), 3.64 (t,J=2.3 Hz, 1H), 4.85 (d, J=2.3 Hz, 2H), 6.37 (d, J=4 Hz, 1H), 7.01 (d,J=8.2 Hz, 1H), 7.11 (d, J=4 Hz, 1H), 7.43 (m, 2H), 10.45 (s, 1H), MS(APCI (−)) m/z 304 (M−H)⁻

EXAMPLE 8tert-butyl[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]acetate

5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-2-carbonitrile(5.4 g, 20 mmol) and tert-butylbromoacetate (4.64 g, 22 mmol) werereacted, according to General Method A, to afford the title compound,m.p. 188-190° C. (3 g, 40%). ¹H-NMR (DMSO-d₆) δ 1.35 (s, 9H), 1.62 (s,6H), 4.8 (s, 2H), 6.35 (d, J=4.3 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.09(d, J=4.3 Hz, 1H), 7.26 (m, 2H), 10.42 (s, 1H), MS (APCI (−)) m/z 380(M−H)⁻

EXAMPLE 9[2-Cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1yl]aceticacid

A solution oftert-butyl[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]acetate(2.2 g, 5.8 mmol), and sodium hydroxide (1.6 g, 40 mmol) in ethanol (200ml) was heated to reflux for 2 hours. After cooling to room temperaturethe mixture was acidified with diluted hydrochloric acid, and extractedwith ethylacetate. The ethylacetate solution was dried over magnesiumsulfate, filtered, and concentrated in vacuo. Recrystallization fromethylacetate/hexane afforded the title compound, m.p. 207-209° C. (1.2g, 64%); ¹H-NMR (DMSO-d₆) δ 1.61 (s, 6H), 4.77 (s, 2H), 6.35 (d, J=4 Hz,1H), 6.98 (d, J=8.1 Hz, 1H), 7.09 (d, J=4.1 Hz, 1H), 7.26 (m, 2H), 10.43(s, 1H), MS (APCI (−)) m/z 324 (M−H)⁻.

EXAMPLE 102-[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]-N-[2-(3-ethoxy-4-methoxyphenyl)ethyl]acetamide

A solution of[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]aceticacid (0.6 g, 1.8 mmol), 3-ethoxy-4-methoxyphenylethylamine (0.36 g, 1.9mmol), diiso-propylethylamine (0.26 g, 2 mmol), andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.7 g, 1.8 mmol) in dimethylformamide (20 ml) wasstirred at room temperature for 20 hours. The mixture was diluted withwater and extracted with ethylacetate. The ethylacetate solution waswashed with brine, dried over magnesium sulfate, and concentrated invacuo. The residue was recrystallized from ethanol to afford the titlecompound, m.p. 160-162° C. (0.2 g, 22%): ¹H-NMR (DMSO-d₆) δ 1.3 (t,J=6.9 Hz, 3H), 1.59 (s, 6H), 2.61 (t, 2H, J=7 Hz), 3.29 (q, J=6.9 Hz,2H), 3.71 (s, 3H), 3.97 (q, J=6.9 Hz, 2H), 4.6 (s, 2H), 6.32 (d, J=5.1Hz, 1H), 6.65 (dd, J=7.6, 2.0 Hz, 1H), 6.77 (d, J=2.3, 1H), 6.83 (d,J=8.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.05 (d, J=4.1 Hz, 1H), 7.26 (m,2H), 8.3 (t, J=6 Hz, 1H), 10.42 (s, 1H), MS (APCI (+)) m/z 503 (M+H)⁺

EXAMPLE 115-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1-pentyl-1H-pyrrole-2-carbonitrile

5-(4,4-Dimethyl-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrrole-carbonitrile(1.94 g, 7.3 mmol) was reacted, according to General Method A, with1-iodopentane (1.5 g, 7.6 mmol) to afford the title compound, m.p.128-131° C. (0.2 g, 8%); ¹H-NMR (DMSO-d₆) δ 0.73 (t, J=7.3 Hz, 3H), 1.05(m, 2H), 1.14 (m, 2H), 1.57 (m, 2H), 1.63 (s, 6H), 4.04 (t, J=7.5 Hz,2H), 6.28 (d, J=4 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 7.04 (d, J=4.5 Hz,1H), 7.33 (dd, J=8.9, 2.0 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 10.41 (s,1H), MS (APCI (−)) m/z 336 (M−H)⁻

EXAMPLE 125-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitril

tert-Butyl2-cyano-5-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate.

To a solution of2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-cyano-pyrrole-1-carboxylicacid tert-butyl ester (0.5 g, 1.4 mmol, 1 eq) in DMF (anhydrous, 25 mL)was added NaH (60% dispersion in oil, 65 mg, 1.6 mmol, 1.2 eq) at 0° C.After 15 min, methyl iodide (0.25 mL, 4.1 mmol, 3 eq) was added and thereaction was allowed to warm to room temperature over night. Thereaction mixture was poured into water (50 mL) and extracted with ethylacetate (2×50 mL). The organic layers were combined, washed with brine(50 mL), dried over magnesium sulfate, filtered and concentrated invacuo to give the product (0.5 g, 94%) as an off-white solid, mp143-145° C.: ¹H NMR (300 MHz, d₆-DMSO) δ 1.38 (s, 9H), 1.62 (s, 6H),3.33 (s, 3H), 6.48 (d, 1H, J=3.8 Hz), 7.13 -7.16 (‘dd’, 1H), 7.33 (d,1H, J=3.8 Hz), 7.40-7.43 (m, 2H). MS (ESI (+)) [M+H]⁺=382. Anal. calcd.for C₂₁H₂₃N₃O₄: C, 66.13; H, 6.08; N, 11.02. Found: C, 65.46; H, 6.16,N, 11.02.

tert-Butyl2-cyano-5-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate(180 mg, 0.47 mmol) was placed in a 25 mL round bottomed flask stopperedwith a rubber septum and equipped with nitrogen inlet and a needle toallow gaseous outflow. A vigorous flow of nitrogen was maintained as theflask was placed in an oil bath and heated to 150° C. After 20 minutesat this temperature, the flask was removed from the oil bath and allowedto cool. To the solid was added acetone/dichloromethane. The solid wasfiltered to give the product (100 mg, 76%) as an off-white solid, mp256-7° C. (dec.): ¹H NMR (300 MHz, d₆-DMSO) δ 1.65 (s, 6H), 3.33 (s,3H), 6.74 (dd, 1H, J=2.6, 3.6 Hz), 7.00 (dd, 1H, J=2.2, 3.8 Hz), 7.15(d, 1H, J=8.5 Hz), 7.67 (d, 1H, J=1.9 Hz), 7.73 (dd, 1H, J=1.19, 8.5Hz), 12.62 (s, 1H). MS (ESI (+)) [M+H]⁺=282. Anal. calcd. forC₁₆H₁₅N₃O₂: C, 68.31; H, 5.37; N, 14.94. Found: C, 67.87; H, 5.42, N,14.75.

EXAMPLE 134-Bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile

To a solution of tert-butyl6-(5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylate(1 eq, 1.94 g, 5.10 mmol) in THF (150 mL) at −78° C. was addedN-bromosuccinimide (1.1 eq, 1.0 g, 5.61 mmol). The solution was allowedto warm and stir for 16 hours. Pyridine (1 mL) was added and the mixturewas poured into water (150 mL), the layers were separated, the aqueouslayer was extracted with ethyl acetate (3 ×10 mL) and the combinedorganic layer was washed with brine, dried over MgSO₄ and concentratedin vacuo. The product, tert-butyl6-(3-bromo-5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylatewas obtained by crystallization from 20% ethyl acetate/hexane as a whitecrystalline solid. ¹H NMR (300 MHz, d₆-DMSO) δ 1.56 (s, 9H), 1.71 (s,6H), 3.65 (s, 3H), 7.30 (s, 1H), 7.44 (d, 1H, J=8.4 Hz), 7.52 (d, 1H,J=8.4 Hz), 7.55 (s, 1H). M/z (ESI (+)) 461 (M+H)⁺. Anal. calcd forC₂₁H₂₂N₃O₄, C, 54.8, H, 4.82, N, 9.13. Found, C, 54.9, H, 4.86, N, 9.1.

A solution of tert-butyl6-(3-bromo-5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylate(1 eq, 0.4 g, 0.87 mmol) in THF was added to a solution of sodiumethoxide (3 eq, 0.18 g, 2.6 mmol) in ethanol (10 mL). The solution washeated at 80° C. for 1 hour, then cooled to room temperature, andconcentrated in vacuo. The residue was dissolved in THF (10 mL) and 4NHCl (10 mL) was added. After heating to 60° C. for 16 hours the solutionwas cooled, poured into water and the layers were separated. The aqueouslayer was extracted with ethyl acetate (3×10 mL) and the combinedorganic layer was washed with brine, dried over MgSO₄ and concentratedin vacuo. The product,4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile(0.17 g, 54%) was obtained by crystallization from 20% ethylacetate/hexane. ¹H NMR (300 MHz, d₆-DMSO) δ 1.64 (s, 6H), 3.62 (s, 3H),7.02 (d, 1H, J=8.2 Hz), 7.34 (s, 1H), 7.35 (dd, 1H, J=1.3, 8.2 Hz), 7.40(s, 1H), 10.47 (s, 1H). MS (ESI (−)) m/z 358/360 (M−H)⁻. Anal. calcd forC₁₆H₁₄N₃O₂Br, C, 53.4, H, 3.92, N, 11.7. Found, C, 52.6, H, 3.82, N,11.2.

EXAMPLE 145-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile

A solution of4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile(70 mg, 0.2 mmol), PhCNPdCl(PPh₃)₂ (cat., 7 mg) and tetramethyltin (10eq, 0.35 g, 2 mmol) in HMPA (3 mL) was heated to 110° C. for 5 days. Thesolution was allowed to cool, poured into water (20 mL) and extractedwith ethyl acetate (3×5 mL). The combined organic layer was washed withbrine, dried over MgSO₄ and purified by flash column chromatography onsilica gel eluting with 30% ethyl acetate/hexane to give5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile(36 mg, 63%) as a white solid. ¹H NMR (300 MHz, d₆-DMSO) δ 1.64 (s, 6H),1.97 (s, 3H), 3.56 (s, 3H), 6.87 (s, 1H), 7.00 (d, 2H, J=8.1 Hz), 7.28(dd, 1H, J=8.1, 1.6 Hz), 7.32 (s, 1H), 10.40 (s, 1H) MS (ESI (−)) 294(M−H)⁻. Anal. calcd for C₁₇H₁₇N₃O₂, C, 69.1, H, 5.8, N,14.2. Found, C,69.1, H, 5.72, N, 14.0.

EXAMPLE 15 tert-Butyl5-cyano-2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-1-carboxylate

To a solution of2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-cyano-pyrrole-1-carboxylicacid tert-butyl ester (3.0 g, 8.2 mmol, 1 eq) in acetic anhydride (50mL) was added Cu(NO₃)_(2.)2.5 H₂O (1.04 g, 4.5 mmol, 0.55 eq). After thereaction mixture stirred at room temperature for 24 hours, it was pouredinto saturated aqueous sodium bicarbonate solution (100 mL) andextracted with ethyl acetate (2×100 mL). The organic layers werecombined, washed with water (50 mL) and brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo. Purification byflash column chromatography (20% ethyl acetate/hexane) on silica gelgave the product as a yellow solid (0.54 g, 16%). ¹H NMR (500 MHz,d₆-DMSO) δ 1.25 (s, 9H), 1.60 (s, 6H), 6.97 (d, 1H, J=8.2 Hz), 7.38 (dd,1H, J=1.8, 8.2 Hz), 7.49 (d, 1H, J=1.8 Hz), 8.09 (s, 1H), 10.47 (s, 1H).MS (ESI (−)) [M−H]⁻ =411. Anal. calcd. for C ₂₀H₂₀N₄O₆: C, 58.25; H,4.89; N, 13.59. Found: C, 58.72; H, 5.14, N, 13.39.

EXAMPLE 164-Amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile

A solution of4-nitro-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile(0.4 g, 1.28 mmol) in ethanol/water (5:1, 20 mL) was treatedsequentially with zinc powder (2.5 wt, 1.0 g) and ammonium chloride (5wt, 2.0 g). The suspension was heated at 80° C. or 30 min, cooled toroom temperature, poured into water (30 mL) and extracted with ethylacetate (3×15 mL). The combined organic layer was washed with brine,dried over MgSO₄ and purified by flash column chromatography on silicagel eluting with ethyl acetate to give4-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile(0.29 g, 80%) as a yellow solid. ¹H NMR (500 MHz, d₆-DMSO) δ 81.63 (s,6H), 4.29 (s, 2H), 6.39 (s, 1H), 6.89 (d, 1H, J=8.1 Hz), 7.49 (s, 1H),7.52 (dd, 1H, J=8.1 and 2.3 Hz), 10.25 (s, 1H), 11.76 (s, 1H). MS (ESI(−)) m/z 281 (M−H)⁻. Anal. calcd for C₁₅H₁₄N₄O₂, C, 63.8, H, 5.00, N,19.9. Found, C, 63.7, H, 5.10, N, 19.82

EXAMPLE 17 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-2-carbonitrile

To4,4-Dimethyl-6-(5-cyano-1H-pyrrol-2-yl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one(0.3 g, 1.2 mmol, 1 eq) in acetic anhydride (7.3 mL) was addedCu(NO₃)₂.2.5 H₂O (0.15 g, 0.65 mmol, 0.55 eq). After the reactionmixture stirred at room temperature for 2 hours, it was poured intosaturated aqueous sodium bicarbonate solution (50 mL) and extracted withethyl acetate (2×50 mL). The organic layers were combined, washed withwater (50 mL) and brine (50 mL), dried over magnesium sulfate, filteredand concentrated in vacuo. The residue crystallized fromdichloromethane/acetone to give the product as a yellow solid (48 mg,13%). The filtrate (0.3 g) was placed aside. ¹H NMR (300 MHz, d₆-DMSO) δ1.65 (s, 6H), 6.94 (d, 1H, J=8.3 Hz), 7.51 (s, 1H), 7.73 (d, 1H, J=8.3Hz), 7.78 (s, 1H), 10.46 (s, 1H), 13.84 (s, 1H). MS (ESI (−)) [M−H]⁻m/z311. Anal. calcd. for C₁₅H₁₂N₄O₄: C, 57.69; H, 3.87; N, 17.94. Found: C,57.91; H, 3.96, N, 17.41.

EXAMPLE 18 3-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile

To5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-2-carbonitrile(0.14 g, 0.45 mmol) in EtOH/H₂O (5:1, 20 mL:4 mL) was added Zn powder(0.35 g, 5.3 mmol) and NH₄Cl (0.70 g, 13 mmol) and the mixture washeated to 60° C. for 25 minutes. After cooling to room temperature andstirring 24 h, the reaction mixture was diluted with ethyl acetate (100mL) and filtered through a pad of celite. The filtrate was washed withwater (50 mL) and brine (50 mL), dried over magnesium sulfate, filteredand concentrated in vacuo. Purification by flash column chromatography(60% ethyl acetate/hexane) on silica gel gave the product as an orangefoam (30 mg, 24%). ¹H NMR (500 MHz, d₆-DMSO) δ 1.63 (s, 6H), 5.01 (s,2H), 5.95 (d, 1H, J=2.9 Hz), 6.87 (d, 1H, J=8.3 Hz), 7.48 (dd, 1H,J=2.0, 8.3 Hz), 7.54 (d, 1H, J=2.0 Hz), 10.30 (s, 1H), 11.17 (d, 1H,J=2.5 Hz). MS (ESI) [M−H]⁻ m/z 281.

EXAMPLE 195-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,3,4-trimethyl-1H-pyrrol-2-carbonitrile

To a solution of5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile(1 eq, 0.15 g, 0.51 mmol) in THF (5 mL) at −78° C. was addedN-bromosuccinimide (1.1 eq, 0.1 g, 0.56 mmol). The solution was allowedto warm and stir for 16 hours. Pyridine (1 mL) was added and the mixturewas poured into water (15 mL), the layers were separated, the aqueouslayer was extracted with ethyl acetate (3×10 mL) and the combinedorganic layer was washed with brine, dried over MgSO₄ and concentratedin vacuo. The product,5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-bromo-1,4-dimethyl-1H-pyrrole-2-carbonitrilewas obtained by crystallization from 20% ethyl acetate/hexane as a whitecrystalline solid. ¹H NMR (300 MHz, d₆-DMSO) δ 1.64 (s, 6H), 1.93 (s,3H), 3.57 (s, 3H), 7.01 (d, 1H, J=8 Hz), 7.31 (dd, 1H, J=1.95, 8 Hz),7.35 (s, 1H), 10.43 (s, 1H). MS m/z (ESI (−)) 372/374 (M−H)⁻. Anal.calcd for C₁₇H₁₆N₃O₂, C, 54.6, H, 4.31, N, 11.2. Found, C, 54.8, H,4.42, N, 11.1.

A solution of5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-bromo-1,4-dimethyl-1H-pyrrole-2-carbonitrile(0.11 g, 0.29 mmol), PhCNPdCl(PPh₃)₂ (cat., 11 mg) and tetramethyltin(10 eq, 0.53 g, 2.9 mmol) in HMPA (3 mL) was heated to 110° C. for 5days. The solution was allowed to cool, poured into water (20 mL) andextracted with ethyl acetate (3×15 mL). The combined organic layer waswashed with brine, dried over MgSO₄ and purified by flash columnchromatography on silica gel eluting with 30% ethyl acetate/hexane togive5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,3,4-trimethyl-1H-pyrrole-2-carbonitrile(77 mg, 85%) as a white solid. ¹H NMR (300 MHz, d₆-DMSO) δ 1.63 (s, 6H),1.87 (s, 3H), 2.49 (s, 3H), 3.50 (s, 3H), 6.99 (d, 1H, J=8.2 Hz), 7.25(dd, 1H, J=8.2, 1.4 Hz), 7.29 (s, 1H), 10.39 (s, 1H). MS (ESI (−)) 308(M−H)⁻. Anal. calcd for C₁₈H₁₉N₃O₄, C, 69.9, H, 6.19, N, 13.6. Found, C,68.8, H, 6.22, N, 12.9

EXAMPLE 204-bromo-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile

To4,4-Dimethyl-6-(5-cyano-1H-pyrrol-2-yl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one(0.625 g, 2.3 mmol, 1 eq) in THF (anhydrous, 60 mL) was added NBS (0.46g, 2.5 mmol, 1.1 eq) at −78° C. After 1 hour, the reaction was warmed toroom temperature, poured into water (100 mL) and extracted with ethylacetate (2×100 mL). The organic layers were combined, washed withaqueous 10% sodium bisulfite solution (50 mL), water (50 mL) and brine(50 mL), dried over magnesium sulfate, filtered and concentrated invacuo. Crystallization from 20% ethyl acetate/hexane gave the product(40 mg, 5%) as a white solid. The filtrate (0.5 g) was placed aside. ¹HNMR (300 MHz, d₆-DMSO) δ 1.64 (s, 6H), 6.98 (d, 1H, J=8.2 Hz), 7.19 (d,1H, J=1.4 Hz), 7.57 (s, 1H), 7.62 (dd, 1H, J=1.4, 8.3 Hz), 10.43 (s,1H), 12.91 (s, 1H). MS (ESI) [M−H]⁻ m/z 344/346. Anal. calcd. forC₁₅H₁₂BrN₃O₂: C, 52.04; H, 3.49; N, 12.14. Found: C, 51.4; H, 3.57, N,11.59.

All publications cited in this specification are incorporated herein byreference herein. While the invention has been described with referenceto a particularly preferred embodiment, it will be appreciated thatmodifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

1. A method of providing progestational therapy to a mammal in needthereof which comprises administering a progestationally effectiveamount of a compound having the structure of formula 1:

wherein: T is S or absent; R₁ and R₂ are each, independently, hydrogen,alkyl, or substituted alkyl; or R₁ and R₂ are taken together to form aring selected from the group consisting of —CH₂(CH₂)_(n)CH₂—,—CH₂CH₂C(CH₃)₂CH₂CH₂—, —O(CH₂)_(p)CH₂—, —O(CH2)_(q)O—, —CH₂CH₂OCH₂CH₂—,and —CH₂CH₂NR₇CH₂CH₂—; n=1-5; p=1-4; q=1-4; R₃ is hydrogen, OH, NH₂,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, or COR^(A); R^(A) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₄ is hydrogen, halogen, CN, NH₂, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R₅ ishydrogen, alkyl, or substituted alkyl; R₆ is hydrogen, alkyl,substituted alkyl, or COR^(B); R^(B) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₇ is hydrogen or alkyl; or a pharmaceutically acceptablesalt thereof, to said mammal.
 2. The method according to claim 1,wherein in formula 1: R₁ and R₂ are each, independently, hydrogen,alkyl, or substituted alkyl; or R₁ and R₂ are taken together to form aring and are —CH₂(CH₂)_(n)CH₂—; R₃ is hydrogen; R₄ is hydrogen orhalogen; R₅ is hydrogen or alkyl; R₆ is hydrogen or alkyl.
 3. A methodof treating or inhibiting breast, uterine, ovarian, endometrial, orprostate cancer in a mammal, which comprises administering a compoundhaving the structure of formula 1:

wherein: T is O, S, or absent; R₁ and R₂ are each, independently,hydrogen, alkyl, or substituted alkyl; or R₁ and R₂ are taken togetherto form a ring selected from the group consisting of —CH₂(CH₂)_(n)CH₂—,—CH₂CH₂CMe₂CH₂CH₂—, —O(CH₂)_(p)CH₂—, —O(CH2)_(q)O—, —CH₂CH₂OCH₂CH₂—, and—CH₂CH₂NR₇CH₂CH₂—; n=1-5; p=1-4; q=1-4; R₃ is hydrogen, OH, NH₂, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, or COR^(A); R^(A) is hydrogen, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R₄ ishydrogen, halogen, CN, NH₂, alkyl, substituted alkyl, alkoxy,substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R₅ ishydrogen, alkyl, or substituted alkyl; R₆ is hydrogen, alkyl,substituted alkyl, or COR^(B); R^(B) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₇ is hydrogen or alkyl; or a pharmaceutically acceptablesalt thereof, to said mammal.
 4. The method according to claim 3,wherein in formula 1: T is O; R₁ and R₂ are each, independently,hydrogen, alkyl, or substituted alkyl; or R₁ and R₂ are taken togetherto form a ring and are —CH₂(CH₂)_(n)CH₂—; R₃ is hydrogen; R₄ is hydrogenor halogen; R₅ is hydrogen or alkyl; R₆ is hydrogen or alkyl.
 5. Themethod according to claim 4, wherein said compound is5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1H-pyrrole-2-carbonitrile;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-prop-2-ynyl-1H-pyrrole-2-carbonitrile;tert-butyl-[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]-acetate;[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]-aceticacid;2-[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]-N-[2-(3-ethoxy-4-methoxyphenyl)ethyl]acetamide;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)1-pentyl-1H-pyrrole-2-carbonitrile;5-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile;4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile;tert-butyl-5-cyano-2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-1-carboxylate;4-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-2-carbonitrile;3-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,3,4-trimethyl-1H-pyrrole-2-carbonitrile;or 4-bromo-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile.
 6. A method of providinghormone replacement therapy to a mammal in need thereof, which comprisesadministering an effective amount of a compound having the structure offormula 1:

wherein: T is O, S, or absent; R₁ and R₂ are each, independently,hydrogen, alkyl, or substituted alkyl; or R₁ and R₂ are taken togetherto form a ring selected from the group consisting of —CH₂(CH₂)_(n)CH₂—,—CH₂CH₂C(CH₃)₂CH₂CH₂—, —O(CH₂)_(p)CH₂—, —O(CH2)_(q)O—, —CH₂CH₂OCH₂CH₂—,and —CH₂CH₂NR₇CH₂CH₂—; n=1-5; p=1-4; q=1-4; R₃ is hydrogen, OH, NH₂,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, or COR^(A); R^(A) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₄ is hydrogen, halogen, CN, NH₂, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R₅ ishydrogen, alkyl, or substituted alkyl; R₆ is hydrogen, alkyl,substituted alkyl, or COR^(B); R^(B) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₇ is hydrogen or alkyl; or a pharmaceutically acceptablesalt thereof, to said mammal.
 7. The method according to claim 6,wherein in formula 1: T is O; R₁ and R₂ are each, independently,hydrogen, alkyl, or substituted alkyl; or R₁ and R₂ are taken togetherto form a ring and are —CH₂(CH₂)_(n)CH₂—; R₃ is hydrogen; R₄ is hydrogenor halogen; R₅ is hydrogen or alkyl; R₆ is hydrogen or alkyl.
 8. Themethod according to claim 6, wherein said compound is5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1H-pyrrole-2-carbonitrile;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-prop-2-ynyl-1H-pyrrole-2-carbonitrile;tert-butyl-[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]-acetate;[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]-aceticacid;2-[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]-N-[2-(3-ethoxy-4-methoxyphenyl)ethyl]acetamide;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)1-pentyl-1H-pyrrole-2-carbonitrile;5-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile;4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile;tert-butyl-5-cyano-2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-1-carboxylate;4-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-2-carbonitrile;3-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,3,4-trimethyl-1H-pyrrole-2-carbonitrile;or4-bromo-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile.9. A method of providing contraception in a mammal in need thereof,which comprises administering an effective amount of a compound havingthe structure of formula 1:

wherein: T is O; R₁ and R₂ are each, independently, hydrogen, alkyl, orsubstituted alkyl; or R₁ and R₂ are taken together to form a ringselected from the group consisting of —CH₂(CH₂)_(n)CH₂—,—CH₂CH₂C(CH₃)₂CH₂CH₂—, —O(CH₂)_(p)CH₂—, —O(CH2)_(q)O—, —CH₂CH₂OCH₂CH₂—,and —CH₂CH₂NR₇CH₂CH₂—; n=1-5; p=1-4; q=1-4; R₃ is hydrogen, OH, NH₂,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, or COR^(A); R^(A) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₄ is hydrogen, halogen, CN, NH₂, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R₅ ishydrogen, alkyl, or substituted alkyl; R₆ is hydrogen, alkyl,substituted alkyl, or COR^(B); R^(B) is hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, aminoalkyl, or substitutedaminoalkyl; R₇ is hydrogen or alkyl; or a pharmaceutically acceptablesalt thereof, to said mammal.
 10. The method according to claim 9,wherein in formula 1: R₁ and R₂ are each, independently, hydrogen,alkyl, or substituted alkyl; or R₁ and R₂ are taken together to form aring and are —CH₂(CH₂)_(n)CH₂—; R₃ is hydrogen; R₄ is hydrogen orhalogen; R₅ is hydrogen or alkyl; R₆ is hydrogen or alkyl.
 11. Themethod according to claim 9, wherein said compound is5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1H-pyrrole-2-carbonitrile;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-prop-2-ynyl-1H-pyrrole-2-carbonitrile;tert-butyl-[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]-acetate;[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]-aceticacid;2-[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]-N-[2-(3-ethoxy-4-methoxyphenyl)ethyl]acetamide;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)1-pentyl-1H-pyrrole-2-carbonitrile;5-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile;4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile;tert-butyl-5-cyano-2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-1-carboxylate;4-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-nitro-1H-pyrrole-2-carbonitrile;3-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile;5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,3,4-trimethyl-1H-pyrrole-2-carbonitrile;or4-bromo-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile.